The treatment of herpes labialis the clinical manifestation of oral-facial infections by type 1 and to a limited extent type 2 herpes simplex viruses (HSV-1 and HSV-2), continues to be a major concern to health practitioners. Because of the localized cutaneous nature of the disease, topical drug administration is the ideal treatment route. Although a few antiviral drugs currently are available, they are not useful in the therapy of herpes labialis due to problems of topical drug bioavailability and/or systemic drug distribution. Recent developments in the molecular biology of herpesviruses have provided new strategies for aniviral chemotherapy. It is now know that herpes simplex virus codes for the important enzyme ribonucleoside diphosphate reductase and it seems clear that this enzyme can serve as a target for antiviral drugs. We have identified certain 2-acetylpyridine thiosemicarbazones which inhibit this enzyme and are potent and selective inhibitors of HSV-1 and HSV-2 replication. At the molecular level, these compounds inhibit cellular functions to a lesser extent than viral functions. In experimental animals, they are able to cross intact skin readily as evidenced by their efficacy in the cutaneous herpes guinea pig model. Consequently, there is excellent potential for the clinical application of these or related derivatives. The goals of this research proposal are to advance our knowledge of how these and newer derivatives act and to develop key compounds for the effective topical treatment of herpes labialis. These objectives will be accomplished through a series of subprojects which will (i) identify new derivatives and their metal chelates of 2-acetylpyridine thiosemicarbazone which selectively inhibit the viral ribonucleotide reductase, (ii) explore the potential to develop synergistic combinations of thiosemicarbazones and known antiviral drugs which act by inhibiting the viral DNA polymerase, (iii) select compounds which will not suppress immune function, (iv) select compounds which are efficacious and do not produce untoward side effects when applied to the skin of guinea pigs, and (v) trace the metabolic disposition of radiolabeled 2-acetylpyridine thiosemicarbazone and identify metabolites. Thus, the first two subprojects will study selected compounds or synergistic combinations of compounds to more clearly elucidate the mechanism by which the viral ribonucleotide reductase is inhibited while the last three subprojects will be used to advance both existing and newer compounds toward clinical trials.